DESCRIPTION: (Applicant's Description) The N-methyl-D-aspartate (NMDA) receptor is involved in many neuronal functions. The research outlined in this proposal is focused upon a powerful form of regulation of the NMDA receptor: the voltage-dependent channel block by external Mg2+. Using the approaches of electrophysiology, kinetic modeling, and molecular biology, the applicant wishes to expand our knowledge of: (1) the characteristics and mechanism of the effects of permeant ions on Mg2+ block of the NMDA receptor in cortical neurons; (2) the NMDA receptor subunit specificity of the permeant ion effects; and (3) the molecular elements that contribute to the permeant ion effects. Since the NMDA receptor is one of the most fundamentally important macromolecules, by virtue of its wide distribution and unique properties, information regarding its basic characteristics will give insight into all the normal and abnormal processes in which the NMDA receptor is involved. Specifically, this research addresses several issues of significance to the physiology and pathology of mental health: (1) This research may shed light on variation in receptor channel function during synaptic transmission, when transient but drastic change occurs in external Na+ concentration. (2) This research may reveal altered receptor function under ischemic conditions, when permeant ion concentrations change from their normal level. (3) This research contributes to the characterization of the ion binding sites of the NMDA receptor which will help us understand the detailed features of this receptor and how its structure results in its unique functional properties.